A wide variety of reaction systems are known for the production of the product of chemical or biochemical reactions. Chemical plants involving catalysis, biochemical fermenters, pharmaceutical production plants, and a host of other systems are well-known.
Systems for housing chemical and biochemical reactions not necessarily for the production of product also are known. For example, continuous-flow systems for the detection of various analytes in bodily fluids including blood, such as oxygen, glucose, and the like are well known.
In many of these and other systems, the capacity of the system (the volume of material that the system is designed to produce, process, or analyze) is adjusted in accordance with the volume of reactant, product, or analyte desirably processed or analyzed. For example, in large-scale chemical or pharmaceutical production, reactors are generally made as large as possible to generate as large a volume of product as possible. Conversely, in many areas of clinical diagnosis, where it is desirable to obtain as much information as possible from as small a physiological sample as possible (e.g., from a tiny drop of blood), it is a goal to minimize the size of reaction chambers of sensors. Several examples of small-scale reactor systems, including those used in clinical diagnoses and other applications, follow.
U.S. Pat. No. 5,387,329 (Foos, et al.; Feb. 7, 1995) describes an extended use planar clinical sensor for sensing oxygen levels in a blood sample.
U.S. Pat. No. 5,985,119 (Zanzucchi, et al.; Nov. 16, 1999) describes small reaction cells for performing synthetic processes in a liquid distribution system. A variety of chemical reactions including catabolic, anabolic reactions, oxidation, reduction, DNA synthesis, etc. are described.
U.S. Pat. No. 5,674,742 (Northrup, et al.; Oct. 7, 1997) describes an integrated microfabricated instrument for manipulation, reaction, and detection of microliter to picoliter samples. The system purported by is suitable for biochemical reactions, particularly DNA-based reactions such as the polymerase chain reaction.
U.S. Pat. No. 5,993,750 (Ghosh, et al.; Nov. 30, 1999) describes an integrated micro-ceramic chemical plant having a unitary ceramic body formed from multiple ceramic layers in the green state which are sintered together defining a mixing chamber, passages for delivering and reacting fluids, and means for delivering mixed chemicals to exit from the device.
Biochemical processing typically involve the use of a live microorganism (cells) to produce a substance of interest. Biochemical and biomedical processing account for about 50% of the total drug, protein and raw amino-acid production worldwide. Approximately 90% of the research and development (R&D) budget in pharmaceutical industries is currently spent in biotechnology areas.
Currently bioreactors (fermentors) have several significant operational limitations. The most important being maximum reactor size which is linked to aeration properties, to nutrient distribution, and to heat transfer properties. During the progression of fermentation, the growth rate for cells accelerates, and the measures required to supply the necessary nutrients and oxygen sets physical and mechanical constraints on the vessel within which the cells are contained. Powerful and costly drives are needed to compensate for inefficient mixing and low mass-transfer rates. Additionally, as metabolism of cells accelerates, the cells generate increased heat which needs to be dissipated from the broth.
The heat transfer characteristics of the broth and the vessel (including heat exchanger) impose serious constraints on the reaction scale possible (see Table 1). While the particular heat load and power requirements are specific to the reaction, the scale of reaction generally approaches limitations as ˜10 m3 as in the case of E. coli fermentation (Table 1). The amount of heat to be dissipated becomes excessive due to limits on heat transfer coefficients of the broth and vessel. Consequently, the system of vessel and broth will rise in temperature. Unfortunately, biological compounds often have a relatively low upper limit on temperature for which to survive (<45° C. for many). Additionally, power consumption to disperse nutrients and oxygen and coolant requirements to control temperature make the process economically unfeasible (see Table 1).
TABLE 1Oxygen- and Heat- Transfer Requirements for E. coli: Effects of ScaleOTRVolumeaPressurePowerHeat LoadCoolantb(mmol/L · h)(m3)(psig)(hp)(Btu/h)(° F.)1501155.084000402001254.9107000403001357.1161000404001356.920800040150101550.288400040200102550.0107800040300103575.7162100022400103577.020960005aLiquid volumebCoolant flow is 35 gal/mm for 1-m3 vessel and 100 gal/mm for 10-m3 vesselcCharles, M. and Wilson, J. Fermentor Design; In: Bioprocess Engineering; Lydersen, B. K., D′Elia, N. A., Nelson, K. L., Ed.; John Wiley & Sons, Inc., New York, 1994.
Aside from reactor scalability, the design of conventional fermentors has other drawbacks. Due to the batch and semi-batch nature of the process, product throughput is low. Also, the complexity and coupled nature of the reaction parameters, as well as the requirement of narrow ranges for these parameters, makes control of the system difficult. Internal to the system, heterogeneity in nutrient and oxygen distribution due to mixing dynamics creates pockets in the broth characterized by insufficient nutrients or oxygen resulting in cell death. Finally, agitation used to produce as homogeneous a solution as possible (typically involving impellar string to simultaneously mix both cells and feeds of oxygen and nutrients) causes high strains which can fracture cell membranes and cause denaturation.
While a wide variety of useful reactors for a variety of chemical and biological reactions, on a variety of size scales exist, a need exists in the art for improved reactors. In particular, there is a current need to significantly improve the design of bioreactors especially as the pharmaceutical and biomedical industries shift increasingly towards bioprocessing.